Medical implant

ABSTRACT

A medical implant is disclosed. The medical implant includes a body having a first end having a first cross-sectional dimension, a second end having a second cross-sectional dimension, and a tapered portion extending between the first end and the second end. The first cross-sectional dimension is larger than the second cross-sectional dimension. In some embodiments, the body comprises multiple layers.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional ApplicationNo. 63/109,615 filed Nov. 4, 2020, and to U.S. Provisional ApplicationNo. 63/241,395 filed Sep. 7, 2021. The contents of each of theseapplications are incorporated by reference herein in their entirety.

BACKGROUND A. Field

This disclosure relates generally to medical implants and methods ofmanufacturing those implants. More particularly, this disclosure isdirected to geometrical configurations and methods of retaining amedical implant within a needle of an implant delivery device.

B. Description of Related Art

When a solution is delivered, injected or otherwise administereddirectly into the eye, the drug quickly washes out or is depleted fromwithin the eye into the general circulation. From the therapeuticstandpoint, this may be as useless as giving no drug at all.Consequently, solid pharmaceutically active implants that providesustained release of an active ingredient have been developed thatprovide delivery within the eye of a relatively uniform concentration ofactive ingredients. Implants are particularly useful for providing ahigh local concentration at a particular target site for extendedperiods of time. These sustained release implants reduce the number ofdoses of the drug to be administered, and avoid the peaks and troughs ofdrug concentration found with traditional drug therapies. Use of abiodegradable drug delivery system that degrades over time has thefurther benefit that the spent implant need not be removed from thetarget site.

An intraocular implant is a drug delivery system configured to delivermedicinal products to the ocular tissue once injected into the eye.Intraocular implants are typically inserted using 22 through 27 gaugeneedles of an implant delivery device. The implants are typicallyretained within the delivery devices using a retention featureincorporated into the design of the delivery device as opposed to theimplant itself. Such systems can result in retention failure where theimplant falls out of the delivery device prior to completion of theimplant procedure.

Prior art implant retention designs and delivery device features alsocan often malfunction such that the delivery of undesired particles fromthe delivery device into the intended site of delivery occurs.

Thus, it would be desirable to provide an implant with improvedretention within the needle of the delivery device that reduces the riskof delivery device-based retention feature failure to ensure that theimplant is secure until deployment and reduces the risk of introducingundesired particulate matter into the patient.

SUMMARY

The following embodiments and aspects thereof are described andillustrated in conjunction with systems, tools and methods which aremeant to be exemplary and illustrative, not limiting in scope.

In one aspect, a medical implant is described. The medical implantincludes a body including a first end having a first cross-sectionaldimension, a second end having a second cross-sectional dimension, and atapered portion extending between the first end and the second end. Thefirst cross-sectional dimension is larger than the secondcross-sectional dimension.

In another aspect, the tapered portion extends only partially betweenthe first end and the second end.

In another aspect, a length of the first end of the body to a first endof the tapered portion is in a range of about 5% to about 50% of thetotal length of the implant.

In another aspect, a length of the first end of the tapered portion tothe second end of the body is in a range of about 950 μm to about 4750μm.

In another aspect, the body of the medical implant comprises a singlelayer.

In another aspect, the body of the medical implant is made of a mixtureof a therapeutic or diagnostic agent and biocompatible polymers. Thenumber and type of biocompatible polymers used, as well as theirrelative concentration can vary depending upon the properties of thetherapeutic or diagnostic agent(s) contained in the medical implant, thelocation and environment in which the implant is to be inserted, anddesired duration the therapeutic or diagnostic agent(s) is to elute fromimplant. Optionally, combinations of 1, 2, 3 or more biocompatiblepolymers can be used in an implant described herein. Particular examplesof biocompatible polymers having applications herein are discussedinfra. The duration the therapeutic or diagnostic agent is to elute fromthe implant can be 1 month, 2 months, 3 months, 4 months, 5 months, 6months, 7 months, 8 months, 9 months, 10 months, 11 months, or a year ormore. Optionally, the biocompatible polymer(s) of an implant describedherein can include terminal esters or acids.

In another aspect, the body of the medical implant comprises a pluralityof layers.

In another aspect, at least one of the plurality of layers is made ofbiocompatible polymers, and at least one other of the plurality oflayers is made of a mixture of a therapeutic or diagnostic agent andbiocompatible polymers.

In another aspect, the medical implant is formed or manufactured using aparticle replication in non-wetting templates (PRINT) method to shapethe medical implant.

In yet another aspect, the medical implant includes a body including afirst layer, a second layer, and a third layer. The body includes afirst end having a first cross-sectional dimension and a second endhaving a second cross-sectional dimension. The first cross-sectionaldimension is larger than the second cross-sectional dimension. The bodyfurther includes a tapered portion extending between the first end andthe second end. Additionally, the first layer and the third layercomprise a first material, and the second layer comprises a secondmaterial.

In addition to the exemplary aspects and embodiments described above,further aspects and embodiments will become apparent by reference to thedrawings and by study of the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments are illustrated in the drawings. It is intendedthat the embodiments and figures disclosed herein are to be consideredillustrative rather than restrictive.

FIG. 1A is a top view of the medical implant of the present application;

FIG. 1B is a cross sectional view of the medical implant prior toinsertion into a medical delivery device;

FIG. 1C is a cross sectional view of the medical implant inserted intothe lumen of the medical delivery device needle;

FIG. 2A is a perspective view of one embodiment of the medical implantshown in FIG. 1A;

FIG. 2B is a perspective view of another embodiment of the medicalimplant shown in FIG. 1A;

FIG. 3A shows a view of the medical implant of FIG. 1A positioned withina drug delivery device;

FIG. 3B shows a top cross-sectional view of the device shown in FIG. 3A;

FIG. 3C shows another view of the medical implant of FIG. 1A positionedwithin a drug delivery device;

FIG. 4 shows a single and multiple medical implants positioned withinthe needle of a drug delivery device;

FIG. 5 shows how implants are retained in a needle based delivery deviceand how they are delivered using a wire pusher wire that when actuatedexceeds the frictional forces between the implants and the needle lumento deliver the implants;

FIG. 6 is an illustration summarizing one possible method used tofabricate PRINT (Particle Replication in Non-wetting Templates) moldscontaining customizable feature geometries and dimensions for thefabrication of implants;

FIG. 7 is a microphotograph showing the top view of a laser etchedSilicon Master showing the geometrical features used to fabricate moldsfor the production of PRINT implants;

FIG. 8 is an illustration summarizing the PRINT molding process used tofabricate implants with customizable geometrical shapes and dimensions;

FIG. 9 shows an apparatus used to measure implant retention force;

FIG. 10 is a graph showing the retention forces of a number of differentshaped medical implants in a 27 G needle;

FIG. 11 illustrates a single die configuration that could be used tofabricate an implant of the present disclosure;

FIG. 12 illustrates a multiplexed die configuration that could be usedto fabricate an implant of the present disclosure;

FIG. 13 illustrates one possible filament die configuration that couldbe used to fabricate an implant of the present disclosure compared to acannula cross-section;

FIG. 14 illustrates a cross-sectional view of an implant made using afilament die;

FIG. 15 illustrates one possible terminal die design that could be usedin an injection molding process to fabricate an implant of the presentdisclosure;

FIG. 16 illustrates cross-sectional views of implants of the presentdisclosure having interference features;

FIG. 17 illustrates one possible compression mold configuration designthat could be used to fabricate an implant of the present disclosure;

FIG. 18 illustrates a cross-sectional view of an implant of the presentdisclosure;

FIG. 19 is a perspective view of one possible design of a deliverydevice that could be used to insert an implant of the present disclosureinto a patient's tissue;

FIG. 20 illustrates a cross-sectional of the delivery device of FIG. 19;and

FIG. 21 is a perspective view of a medical implant having a surfacemodification.

DETAILED DESCRIPTION

A medical implant for use with a needle-based implant delivery device isdisclosed. The medical implant is characterized by a geometrical shapethat includes an outer geometry designed to create an interference fitbetween the inner diameter of the needle or cannula positioned adjacentto a needle and the outer surface area of the implant so that theimplant is retained within the needle from the time of manufacture upuntil the implant is inserted and dosed to a patient's tissue. Retentionwithin the needle is maintained during packaging, shipping, and storageof the loaded implant delivery device.

FIG. 1A shows an example medical implant 100 for use with a needle-baseddelivery device to deliver the medical implant into a patient's body. Inone possible embodiment, the medical implant is an intraocular implantcontaining a drug, i.e., an active pharmaceutical ingredient (API). Themedical implant 100 has an outer shape or geometry which creates africtional force within the drug delivery device large enough to retainthe implant within the drug delivery device during manufacturing,packaging, shipping, and storage of the device, but allows for therelease, delivery, insertion, or implantation of the implant duringadministration from the delivery device into a patient's tissue uponactivation of the delivery device at the time of administration.

As shown in FIG. 1A, the medical implant 100 includes a body 102 havinga first end 104 and a second end 106. In one embodiment, the first end104 has a greater or larger cross-sectional dimension W1 than thecross-sectional dimension W2 of the second end 106, so that the firstend 104 is retained within the drug delivery device by frictionalinterference with the interior surface of the needle. As shown in FIG.1A, the first and second ends 104, 106 may have a rounded profile 104A,106A. In other embodiments, the profiles of the first and second ends104, 106 may take other geometrical forms, such as rectangular prisms.

FIG. 1B shows a cross section of region L1 of the medical implant 100prior to being loaded into the medical device with a largest diagonallength D1. D1 is related to W1 and H1 by the relationship, D1=√{squareroot over (H1 ²+W1 ²)}.

D1 is preferably predetermined and configured to be greater than anominal inner diameter (ID) of the needle that it will be inserted intoand retained therein (see FIG. 1C). In some embodiments, D1 has a lengthof 104% of the nominal inner diameter (ID) of the needle that it isretained in, which may be in the range of about 105% to about 102.5% ofthe nominal ID of the needle. In some embodiments, D1 has a length of102.5% of the nominal inner diameter (ID) of the needle that it isretained in, which may be in the range of about 104 to about 100.5% ofthe nominal ID of the needle. For 27G needles, the ID may be in therange of about 292.1 μm to about 330.15 μm. For 25G needles, the ID maybe in the range of about 393.7 μm to about 431.8 μm. The implants ofthis this disclosure can be configured to be retained in needle sizes inthe range of from 21G to 30G.

Referring again to FIG. 1A, in some embodiments, the length L of thebody 102 may be in the range of about 1000 μm to about 5000 μm. In someembodiments, the body 102 includes a tapered portion 108 extendingbetween the first end 104 and the second end 106. In some embodiments,the tapered portion 108 extends only partially between the first end 104and the second end 106. For example, the tapered portion 108 begins atsome midpoint M 110 between the first end 104 and the second end 106. Inone example embodiment, a length L1 of the first end 104 of the bodyextends to the midpoint 110, which is also a beginning end of thetapered portion 108, and can be in a range of about 5% to about 50% ofthe total implant length L. Similarly, a length L2 of the second end 106of the tapered portion 108 starting from the midpoint 110 andterminating at a second end 112 of the tapered portion 108 is in a rangeof about 10% to about 90% of the total implant length L. In someembodiments, the tapered portion 108 may define the entire the secondend 106 of the body 102.

In one embodiment, the medical implant 100 is monolithic, or comprises asingle layer, as shown in FIG. 2A. In this embodiment, the medicalimplant 100 may be comprised of a therapeutic agent, dexamethasone, forexample and poly(D, L-lactic-co-glycolic acids)(PLGAs), for example. Inother embodiments, the medical implant may be comprised of a mixture ofa therapeutic agent, monotosylate((S)-4-(3-amino-1-(isoquinolin-6-yl-amino)-1-oxopropan-2-yl)benzylalcohol monotoluenesulfonate;(S)-3-amino-2-(4-(hydroxymethyl)phenyl)-N-(isoquinolin-6-yl)propanamidemonotosylate), for example and polyesteramide (PEA) polymers or anyother suitable materials.

Prostaglandins, and analogs or derivatives thereof, having applicationsas a therapeutic agent in a pharmaceutical implant composition of thepresent disclosure include latanoprost, bimatoprost, travoprost,tafluprost, 3-hydroxy-2,2-bis(hydroxymethyl)propyl7-((1r,2r,3r,5s)-2-((r)-3-(benzo[b]thiophen-2-yl)-3-hydroxypropyl)-3,5dihydroxycyclopentyl)heptanoate (chemical structure (II)), cloprostenolisopropyl ester, 13,14-dihydrocloprostenol isopropyl ester,latanoprostene bunod, unoprostone, PGF_(1α) laisopropyl ester, PGF_(2α)a isopropyl ester, PGF_(3α) isopropyl ester, fluprostenol, or anycombination thereof. In some embodiments, the prostaglandins, andanalogs or derivatives thereof, having applications as a therapeuticagent include dukeprost, tiaprost, or both. In some embodiments, theprostaglandins, and analogs or derivatives thereof, having applicationsas a therapeutic agent include free acids, and pharmaceuticallyacceptable salts thereof, of the prostaglandins and analogs orderivatives thereof.

Other therapeutic agents having applications in a pharmaceutical implantcomposition of the present disclosure for treating an ocular disease ordisorder, e.g. glaucoma, include but are not limited to beta blockers,miotics, alpha adrenergic agonists, or carbonic anhydrase inhibitors,and antimetabolites such as 5-fluorouracil or mitomycin C.

Naturally, a pharmaceutical composition of the present disclosure cancomprise a therapeutic agent, or a combination of two or moretherapeutic agents, examples of which are discussed above. Moreover,analogs or derivatives, pharmaceutically acceptable salts, zwitterions,solvates, esters, and polymorphs of therapeutic agents, such as thosediscussed herein, have applications in a pharmaceutical composition ofthe present invention. As used herein, an “analog” is a compound havinga structure similar to that of another compound (its “parent” compound)but differing from it in respect to a certain component. The analog candiffer from its parent compound in one or more atoms, functional groups,or substructures, which are replaced with other atoms, groups, orsubstructures. Likewise, an analog of a parent compound can also beformed from the replacement of particular atoms of the parent compoundwith radioactive isotopes of those particular atoms. A “derivative” is acompound that can be imagined to arise or actually be synthesized from aparent compound by replacement of one atom with another atom or group ofatoms.

In a pharmaceutical composition of the present disclosure, a therapeuticagent is blended with a biodegradable polymer matrix to form apharmaceutical composition. The amount of a therapeutic agent used inthe pharmaceutical composition depends on several factors such as: biodegradable polymer matrix selection, therapeutic agent selection,desired rate of release in a substantially linear manner, duration ofdesired rate of release, configuration of pharmaceutical composition,and ocular PK, to name a few.

For example, overall therapeutic agent content of a pharmaceuticalcomposition of the present disclosure may comprise approximately about0.1 to approximately 60.0 weight percent of the total pharmaceuticalcomposition. In some embodiments, the therapeutic agent comprises fromabout 1% to about 90%, or about 1% to about 80%, or about 1% to about70%, or about 1% to about 60%, or about 1% to about 50%, or about 1% toabout 40%, or about 1% to about 30%, or about 1% to about 20%, or about1% to about 10%, or about 10% to about 50%, or about 10% to about 40%,or about 10% to about 30%, or about 10% to about 25%, or about 10% toabout 23%, or about 10% to about 20%, or about 15% to about 35%, orabout 15% to about 30%, or about 15% to about 25%. All these percentagesare in weight percentage. In a particular embodiment, dexamethasonecomprises approximately 20.0 weight percent of the pharmaceuticalcomposition.

A pharmaceutical composition of the present disclosure is prepared bydissolving a polymer matrix and therapeutic agent in a suitable solventto create a homogeneous solution. For example, acetone, alcohol (e.g.,methyl alcohol or ethyl alcohol), acetonitrile, tetrahydrofuran,chloroform, and ethyl acetate may be used as solvents. Other solventsknown in the art are also contemplated. The solvent is then allowed toevaporate, leaving behind a homogeneous film. The solution can beaseptically filtered prior to evaporation of the solvent.

Additional implant formulation examples can be found in U.S. Pat. No.10,624,904, which is fully incorporated by reference herein in itsentirety.

In another embodiment, the medical implant 100 may be comprised of aplurality of layers. In one example, as shown in FIG. 2B, the medicalimplant 100 includes a first layer 110, a second layer 120, and a thirdlayer 130. The second layer 120 is disposed between the first layer 110and the third layer 130. In some embodiments, the first layer 110 andthe third layer 130 are made of the same material. In some embodiments,the first layer 110 and the third layer 130 are comprised of a mixtureof PLGAs, and the second layer 120 may be comprised of a mixture ofDexamethasone or other therapeutic drugs and PLGAs, for example. Inother embodiments, the first layer 110, the second layer 120, and thethird layer 130 may be comprised of any other suitable materials.

Although the medical implant 100 is shown as having three layers, itshould be understood that in other embodiments, the implant may compriseany number of layers.

FIGS. 3A, 3B, and 3C show the medical implant 100 positioned within aneedle of a needle-based drug delivery device 200, where the needle canrange in size from 21G to 30G. As shown in FIGS. 1B, 3B, and 4 thegeometrical shape, i.e., its outer geometry, of the medical implant 100creates an interference fit with the inner diameter 202 of the needle200 to retain the implant 100 within the needle.

In another embodiment, multiple medical implants 100 can be insertedinto a single delivery device DD, as shown in FIG. 4, in order toincrease the amount of medicinal product delivered, to deliver one ormore medicinal products, or to deliver implants designed and configuredto have one or more drug delivery profile.

FIG. 5 show examples of how implants are retained in a needle-baseddelivery device, and how they are delivered using a pusher wire thatwhen actuated exceeds the frictional forces between the implants and theneedle lumen to deliver the implants. The pusher wire may be propelledor actuated using a spring based, electro-mechanical based or pneumaticbased device feature.

A number of possible devices can be configured and used to deliver theimplants of the present application. For example, FIGS. 19 and 20 showone possible embodiment of a delivery device 100 having an elongatedsubstantially cylindrical body or housing 1 defining a longitudinal flowpath or axis 105, the delivery device has a distal end 110 and aproximal end 120. The housing 1 can be formed from sections, for exampletwo halves 1 a and 1 c, that are permanently connected to each otherduring assembly of the device. When assembled, the housing 1 can have agenerally tapered proximal end 8 that provides an ergonomic benefit whenholding and using the device to deliver the implant into tissue. Thetapered proximal end can also provide a convenient prompt to the user ofwhere on the housing to grasp/hold the delivery device. To furtherindicate where the user should grasp or hold the delivery device duringuse, the outer surface of the distal end of housing 1 can have a gripsurface 6. This grip surface can be comprised of a plurality of surfacesin the form of raised or proud surfaces or ribs, knurled or roughenedsurfaces, inlays or overlays of a tactile/soft touch material, stipplingfeatures, dimples, or any other features that indicates to the userwhere to grab or hold the device during use. Another feature of gripsurface 6 is that it can provide a pushing or bearing surface that theuser can use to deploy the device axially in the distal direction duringinsertion of the needle at the desired implant insertion location site.Another device feature that can assist a user in moving or pushing theneedle into the target tissue location is the raised surface of theactivation member 5. In some cases, it is desirable to include a pushingsurface 9 that provides the user a tactile feel and/or leverage featureduring operation of the implant delivery device 100.

The housing 1 can also have a cut-out located at the distal end portionthat will slidably accept lock 3 having an anvil stop surface and aretaining detent that can be configured to engage a portion of thehousing 1 to prevent premature or unintended disengagement from a lockedposition. Lock 3 is configured to have two positions, a locked positionand an unlocked position. FIGS. 19 and 20 show the lock 3 in the firstor locked position where the anvil stop surface abuts and preventsmovement of the activation member 5, which in turn prevents activationof the implant delivery device. The second or unlocked position is wherethe user has removed and physically separated lock 3 from the housing 1,for example by pulling the lock transversely relative to thelongitudinal axis 105 to overcome the reversible retaining detent. Oncelock 3 is removed from the delivery device 100, the activation member 5is no longer blocked from moving relative to both the housing and theshuttle assembly 14, more specifically shuttle 18. When in the first orlocked position, lock 3 can function as anti-rolling feature. i.e., theprotruding structure of the lock will prevent the delivery device fromuncontrollably rolling on a flat surface, such as, inadvertently rollingoff a tabletop. A gripping tab can be provided that extends radiallyfrom the lock past the outside surface of the housing and is shaped sothat a user can grasp lock 3 to remove it from housing 1.

Other examples of delivery devices include, but are not limited to, thedevices shown and described in U.S. Pat. Pub. No. 2019/0374380, U.S.Pat. Nos. D592,746, 9,039,761, and 10,258,503.

One possible method of manufacturing or forming the medical implant 100is a particle replication in non-wetting templates (PRINT) method andtechnology to obtain the shaped medical implants 100 of this disclosure.The geometric shape of the medical implant 100 can be easily changedduring the manufacturing process by changing the geometry of the moldtooling features used to form the implants using PRINT technology.

FIG. 6 illustrates the top view of a PRINT mold feature whose geometrycan be modified to produce implants with different geometrical shapes,as further described in U.S. Pat. No. 10,624,904, the teachings of whichare incorporated fully herein by reference.

FIG. 7 and FIG. 8 show the stepwise process used to make implants withcustomizable geometries for the fabrication of micron sized medicalimplants. In the PRINT manufacturing process, a flexible elastomer moldis designed to have a cavity matching the 2-D planar projection of theimplant. A rigid material is etched or machined to produce an array offeatures of a consistent depth with a repeating planar X and Y axisdesign having one end of the prism of a larger diagonal than the ID ofthe delivery needle and one end of the prism tapered to a smallerdiagonal than the ID of the delivery needle. The rigid mold isreplicated to create a flexible template consisting of inverted featuresthat can be described as posts. The flexible template is replicated tocreate the flexible mold or tooling consisting of cavities. The flexibletemplate and flexible mold are designed so that it is easy for materialsto release from their surfaces. To produce the implants using the PRINTmanufacturing technique, the matrix material is heated, and pressure isapplied to a laminate of the flexible mold, the matrix material film,and a flexible substrate. The matrix material fills the flexible moldcavities as the laminate is heated and compressed. The flexible mold isreleased from the matrix material to present an array of the taperedprism features adhered to a flexible substrate.

Further details of the PRINT method and technology are described indetail in U.S. Pat. Nos. 7,976,759, 8,439,666, 8,662,878, 8,944,804,8,945,441, 9,314,548, 9,340,001, 9,545,737, and 9,662,809, all of whichare incorporated by reference herein in their entireties.

Further methods to fabricate the tapered prism or trapezoidal prism orwedge style prism shaped implant of the present disclosure includedie-formed extrusion, filament extrusion, injection molding, compressionmolding and stamp molding. These methods can produce an implant having aportion of the prism length with a larger diagonal dimension than theinner diameter (ID) of the delivery needle and a portion of the prismlength with a smaller diagonal than the ID of the delivery needle. Thedesign of a two-dimensional (2-D) form can serve as one possiblestarting point for different manufacturing techniques. A 2-D formdefines the perimeter of the target shape, and another processing stepcan then be used to control the undefined third dimension which can bereferred to as the z-dimension or z-axis. Still other manufacturingtechniques can utilize a three-dimensional design e.g., 3-D Printing,Layer by Layer manufacturing, or additive (lamination) manufacturing.Still more manufacturing techniques can combine a coating or additivemanufacturing process and 2-D form manufacturing techniques to create animplant with a portion of the length of the shape having a diagonal ordiameter larger than the ID of the delivery needle and a portion of thelength of the shape that has a diagonal or diameter smaller than the IDof the delivery needle.

The initial step of creating a 2-D shape is to fabricate a die, or tool,to form the implant matrix material. This can be accomplished bymachining or etching metal, ceramic, silicon, or other known tool makingmaterials. These materials can hold their shape when processed.

For die extrusion, a 2-D projection of the X and Y planar design wouldbe etched to make the die opening shape as exemplified in FIG. 11. Thematrix material would be pushed through the die shape using acombination of heat and pressure. The pressure could be pneumaticallyactuated or mechanically driven using intermeshed screws. To achieveappropriate control of the heat applied to the matrix material, anelectrical heating element would be used. The material could be fed to adie with a single opening. A die could be constructed to have multipleopenings of the same planar design to increase throughput as in FIG. 12.Each opening would be fed by the same matrix material. Alternatively, adivided matrix feed pathway could be used to coextrude multipleformulations within a single extruded geometry. The coextrusion could beused to create a wedge shaped form of one of the matrix componentsexpanded after the die to generate a section of the 3-D shape largerthan the ID of the dosing needle cannula.

For filament extrusion the matrix material could be mixed using anextruder as described above for die extrusion. A filament die of adiameter that is larger than the ID of the target needle cannula wouldbe attached to the end of the extruder barrel. FIG. 13 depicts anexample comparison between the larger filament die and the target needlecross-section view. The circular extrudate from the extruder would bedrawn using variable extensional stress to achieve the tapered filamentsections along the length of the extrudate. See FIG. 14 for an exampleof the side profile depiction of the filament extrudate. Using a cuttingmechanism, the filament extrudate would be cut into sections to produceimplants of a controlled length. The filament extrudate would have adiameter narrower than the target needle cannula to provide a sufficientlead-in to the target delivery needle during the loading of the implantinto the needle cannula. The filament extrudate would have increasinglythicker diameter moving from the narrow or tapered end of the cutsection to the interference end of the cut section.

For an injection molding process to form the implant of the presentdisclosure, the rigid mold would have a cavity feature that projectedthe 2-D planar view of the intended implant geometry. The mold and theindividual cavities could be machined, or 3-D printed, to produce thefinal shape. The cavities would have a tapered profile to produce acylindrical or prism shape having one end of the cylinder or prismsmaller than the ID of the delivery needle and one end of the cylinderor prism larger than the ID of the delivery needle. FIG. 15 illustratesone possible design of an injection molding die.

When injection molding is used to fabricate the implants of the presentdisclosure, any number of cavities per injection molding dies can beused. The sprue and runner configuration of the injection molding diewould be designed to have channel diameter reduction based on proximityto the terminal cavities. The terminal connection can be placed so thatthe flashing from the removal of the individual part would not alter theside profile of the implant. An example of the connection placement thatwould not alter the side profile would be at the top tip end or bottomtip end of the implant, see FIG. 15. The design of the injection moldingdie also allows for the introduction of an interference feature alongthe side profile of the implant cavity, for example a flange design. Theinterference feature could be designed to provide a controlled amount ofresistance for retention and controlled amount of resistance forejection speed. The interference feature would make the implant diameteror diagonal profile larger than the ID of the delivery needle. Theinterference feature could be a continuous feature around thecircumference or perimeter of the implant, or it could be adiscontinuous feature on the circumference or perimeter of the implant,e.g., a feature on one face of a prism or one point along thecircumference of a cylinder. FIG. 16 shows an example of a continuousinterference feature and discontinuous interference feature.

For compression or stamp molding, the rigid mold or die is designed tohave a cavity matching the 2-D planar projection of the desired implant.The rigid material is etched or machined to produce an array of featuresof a consistent depth with a repeating planar X and Y axis design havingone end of the prism of a larger diagonal than the ID of the deliveryneedle and one end of the prism tapered to a smaller diagonal than theID of the delivery needle (see FIG. 17). The matrix material is heatedusing a temperature-controlled heating element and compressed using apressure-controlled press that can use pneumatics or hydraulics.Compression or stamp molding involves the use of 2 rigid platens thatare brought together to fill the die cavities with the matrix material.The die design could be a flat surface mated with a patterned moldplaten. Alternatively, the die design could involve a patterned array ofcavities on both mold platens where the combined depth of the cavitieson each mold face equals the target implant thickness in the z-axis.After the platens achieve complete compression, the matrix cools and isreleased from the mold cavities.

For 3-D printing or Layer-by-Layer manufacturing, the construction ofthe implant utilizes precise spatial deposition of the matrix material.The precise spatial deposition of matrix material is typically achievedthrough robotics, automation, and computer assisted drawings. A computerassisted drawing would be generated of an implant. The implant designwould incorporate one end of the implant having a maximum diagonal ordiameter larger than the ID of the delivery needle and one end of theimplant having a maximum diagonal or diameter smaller than the ID of thedelivery needle. The manufacturing technique for creating the implantusing filament dispensing stylus would involve a dispensing tip with adiameter smaller than the smallest implant design feature. For a similartechnique as in layer-by-layer manufacturing, the z-dimension resolutionof the layer features must be less than the target thickness of theimplant. The minimum resolution criteria enable the creation of theinterference zones and non-interference zones along the implant'slength.

Regardless of the method used to fabricate the implants of the presentdisclosure, there are post-processing modifications that are possibleusing the previously mentioned manufacturing modalities to create asection of the implant with one or more interference features. Theinitial size of the implant generated by the initial fabricationprocedure would be smaller than the target cannula ID. Applying amaterial that has the capacity to increase in size in the presence of aspecific media (e.g., hydrogels that increase in volume in the presenceof water) onto the end of an implant loaded in a needle cannula. Theselective addition of the second material would create the two distinctportions of the implant design where one portion of the prism length hasa larger diagonal than the ID of the delivery needle. A manufacturerwould fabricate the implant with a sub-needle ID diameter or diagonalusing any of the techniques mentioned above. A section of the implantlength would be coated with a swelling media through various techniquese.g., submersion, spray-drying, slot die coating, or vapor deposition.The swelling media can be applied as a liquid and dried or cross-linkedto form a solid coating.

The implant shape can be described using six parameters, namely, overalllength, thickness, interference width, slip width, interference length,and slip length. These six implant design parameters impact the drugproduct performance through three key responses. In FIG. 18, four of theparameters are shown and overall length is not shown but would be theimplant length from end-to-end including both rounded end. Thicknesswould be captured by a projection into the z-axis. The three keyresponses are: (1) the resistance during loading of the implant in thedelivery needle, (2) the implant's retention in the delivery needle orthe resistance to movement of the implant while the implant is loaded inthe delivery needle, (3) the resistance to ejection when the implant isdelivered out of the needle.

The overall length and thickness parameters have a positive correlationwith the three responses mentioned above. As the overall length orthickness increases, the amount of implant surface that can be incontact with the delivery needle wall or inner surface also increases.The interference width parameter correlates positively with theresistance to loading. As the interference width increases the implantdiagonal increases, and the resistance during loading increases as aresult. The implant's resistance to movement within the delivery needleand the implant's resistance to ejection increases with interferencewidth until the implant's diagonal matches the ID of the deliveryneedle. At interference widths where the implant diagonal is above theID of the delivery needle, there is no practical difference in theimplant's retention performance or the resistance to ejection. Due tothe shearing of material from the edges of the implant as the implant isloaded into the delivery needle, the implant's diagonal does not changeonce it is in the delivery needle. Once inside the delivery needle, theimplant's resistance to movement and the implant's resistance toejection do not change because the implant's diagonal has been reducedto match the ID of the delivery needle.

The interference length parameter correlates positively for all threeresponses. Greater interference length increases the resistance toloading, retention, and ejection based on the same rationale as theoverall length and thickness. The slip width parameter impacts theloading resistance. The incorporation of the slip section or tapereddesign creates a lead-in to make implant loading easier. The slip widthshould not be so small that the mechanical strength is compromisedduring routine manufacturing processes including loading and ejection.The implant is preferably designed to withstand pushing another implantwithin the delivery needle or being pushed by a pusher wire for loadingor ejection. However, if slip width is large or too similar to thedelivery needle ID, then the resistance to loading increases andmechanical failure of the implant during loading may occur. The slipwidth cannot exceed the ID of the delivery needle. In other words, theslip length parameter impacts the resistance to loading of the implantand is negatively correlated. A properly predetermined slip widthparameter should make the process of loading the implant into the needlecannula easier because resistance to loading decreases as the sliplength increases. As the implant is loaded, the slip section of theimplant centers the implant in relation to the delivery needle openingbecause the slope of the tapered prism forces the implant to orient andmove parallel to the delivery needle cannula the further the implanttravels into the delivery needle. Smaller slip lengths have the sameimpact on the three responses as larger interference lengths. Smallerslip lengths increase the resistance to loading, movement within thedelivery needle, and ejection from the delivery needle.

Determination of implant retention force within a needle cannula can beobtained by measuring the force required to eject the implants from thelumen of the delivery needle, e.g., a 27G needle. Using a narrow-gaugestainless-steel pusher rod operatively associated with a Mark-10 ModelM5-10 Force Gauge, or similar force gauge, and a load cell, will providean indication of the pusher wire force necessary to eject the implantfrom the inside of the needle cannula. FIG. 9 shows one example of anapparatus used to measure implant retention force. The steel pusher wireis inserted into the needle containing the implant, and advanced untilthe implant is disengaged from the needle. The force required todisengage the implant is measured as the retention force by the loadcell.

FIG. 10 is a graph showing the retention force measurements of a numberof medical implants with different shapes in a 27 G needle. Thenumerical results and information about the implants tested aresummarized in Table 1 below for implants in 27G needles.

Needle Gauge: 27 G Ultra-thin wall needle Sample Group: A B C D E F1 F2Manufacturing Injection Injection Injection PRINT PRINT PRINT PRINTProcess: mold mold mold Implant Cylinder Cylinder Cylinder Wedge ShapedWedge Shaped Rectangular Rectangular Geometry: Prism Prism Polymer Used:PEA PEA PEA PLGA PEA PEA PEA Drug Present: Yes Yes Yes No Yes Yes YesNominal 280D × 280D × 280D × 210D × 210D × 220D × 220D × Dimension (μm):1500L 1500L 3000L 225/200W × 222/200W × 220W × 220W × 2275L 2350L 2925L4500L Interference 0 0 0 481 489 2925 4500 Length (μm): MeasuredRetention 265 270 270 316 338 341 345 Dimension (μm): Nominal Needle 311311 311 311 311 311 311 ID (μm): Ret Dim/Needle 0.85 0.87 0.87 1.02 1.091.10 1.11 ID: Retention Force (N) 0.000 0.060 0.002 0.060 0.100 1.0001.000 0.002 0.000 0.012 0.090 0.158 0.010 0.000 0.026 0.030 0.072 0.0120.042 0.024 0.040 0.058 0.004 0.108 0.004 0.170 0.260 0.010 0.006 0.0100.080 0.002 0.000 0.006 0.050 0.006 0.004 0.000 0.080 0.000 0.012 0.0000.008 0.000 0.004 0.000 0.000 0.018 0.024 0.022 0.066

The test results show that the implant 100 of the present application(wedge shape) had the best retention force (over 0.350 lb) out of theseven different designs tested. The retention forces of the designs withuniform diameters were either too low (cylinder) and disengaged tooeasily, or too high (rectangular prism) and did not fit into the lumenof the needle.

In operation, the medical implant 100 is used in conjunction with a drugdelivery device, such as a needle 200, to inject (insert) the medicalimplant 100 into a patient's tissue. In one example embodiment, themedical implant 100 is an intraocular lens implant configured to beinjected into the posterior chamber of a patient's eye. First, theneedle of the delivery device is inserted through the sclera of theposterior chamber. The implant(s) are then mechanically delivered intothe posterior chamber by the forward motion of a pusher wire in thelumen of the needle, as shown in FIG. 5. The motion of the pusher wiremay be driven by a variety of delivery device features, including metalor plastic springs or pneumatically. Actuation of this deliverymechanism may be accomplished by linking the delivery mechanism to apush button or slide on the device handle that is operated by thephysician performing the procedure.

Another aspect of the implants of the present disclosure is the abilityto impart a surface modification (see FIG. 21—200, 210) to create aninterference surface of the medical implant 100. Such surfacemodification can enhance and optimize the retention force when theimplant is loaded into a needle cannula. Examples of surfacemodifications can include coatings, films, biomatrices, nanostructures(nanotubes and nanopores), roughened, sputtered, and sprayed surfaces onboth macro and nano scales. The rugosity or roughness of the implantsurface could also be accomplished by including these texture featuresin the mold tools used to form the implants. Coatings and films couldinvolve the use layering techniques applied to the surface of theimplants, possibly using a combination of different polymers or othercoating materials having different surface energies relative to thelumen of the contacted delivery device surfaces. Combinations ofdifferent surface modifications can also be used, for example, one typeof surface modification 200 on one portion of the implant 100 andanother surface modification 210 used on a different portion of theimplant.

While a number of exemplary aspects and embodiments have been discussedabove, those of skill in the art will recognize that still furthermodifications, permutations, additions and sub-combinations thereof ofthe features of the disclosed embodiments are still possible.

1. A medical implant comprising: a body including a first end having afirst cross-sectional dimension, a second end having a secondcross-sectional dimension, and a tapered portion extending between thefirst end and the second end; wherein the first cross-sectionaldimension is larger than the second cross-sectional dimension.
 2. Themedical implant of claim 1, wherein the tapered portion extends onlypartially between the first end and the second end.
 3. The medicalimplant of claim 1, wherein the first end and the second end each have arounded profile.
 4. The medical implant of claim 1, wherein a length ofthe first end of the body to a first end of the tapered portion is in arange of about 5% to about 50% of the total length of the implant. 5.The medical implant of claim 1, wherein a length of the first end of thetapered portion to the second end of the body is in a range of about 950μm to about 4750 μm.
 6. The medical implant of claim 1, wherein the bodyof the medical implant comprises a single layer.
 7. The medical implantof claim 1, wherein the body of the medical implant is made of a mixtureof a therapeutic or diagnostic agent and biocompatible polymers.
 8. Themedical implant of claim 7, wherein the biocompatible polymers inclideterminal esters or acids.
 9. The medical implant of claim 1, wherein thebody of the medical implant comprises a plurality of layers.
 10. Themedical implant of claim 9, wherein at least one of the plurality oflayers is made of biocompatible polymers, and at least one other of theplurality of layers is made of a mixture of a therapeutic or diagnosticagent and biocompatible polymers.
 11. The medical implant of claim 1,wherein the medical implant is formed or manufactured using a particlereplication in non-wetting templates (PRINT) method to shape the medicalimplant.
 12. The medical implant of claim 1, wherein the medical implantis inserted using a drug delivery device.
 13. The medical implant ofclaim 1, wherein the body of the medical implant includes a surfacemodification.
 14. A medical implant comprising: a body including a firstlayer, a second layer, and a third layer, wherein the body furtherincludes a first end having a first cross-sectional dimension and asecond end having a second cross-sectional dimension; the body furtherincluding a tapered portion extending between the first end and thesecond end; wherein the first layer and the third layer comprise a firstmaterial, and the second layer comprises a second material; and whereinthe first cross-sectional dimension is larger than the secondcross-sectional dimension.
 15. The medical implant of claim 14, whereinthe tapered portion extends only partially between the first end and thesecond end.
 16. The medical implant of claim 14, wherein a length of thefirst end of the body to a first end of the tapered portion is in arange of about 5% to about 50% of the total length of the implant. 17.The medical implant of claim 14, wherein the first material comprises amixture of PLGAs and the second material comprises a mixture of atherapeutic agent and PLGAs.
 18. A drug delivery device configured toinsert one or more of the medical implant of claim 14 into an eye of apatient, the drug delivery device comprising a needle configured toretain the medical implant from a time of manufacture until the medicalimplant is inserted into the eye of the patient.
 19. The drug deliverydevice of claim 18, wherein the medical implant is retained within theneedle via a friction fit.
 20. A method for manufacturing a medicalimplant, comprising: forming a medical implant using a particlereplication in non-wetting templates (PRINT) method to shape the medicalimplant, the medical implant comprising body including a first endhaving a first cross-sectional dimension, a second end having a secondcross-sectional dimension, and a tapered portion extending between thefirst end and the second end, wherein the first cross-sectionaldimension is larger than the second cross-sectional dimension; whereinthe shape of the medical implant enables the medical implant to beretained within a needle of a drug delivery device via a friction fit;and wherein the medical implant is configured to be inserted into an eyeusing the drug delivery device.